The purpose of this study is to determine if the exposure to acute or chronic ethanol increases natural killer (NK) activity of immune cells. Acute exposure to ethanol has been reported as an inhibitory of NK activity in vitro. However, we have found that chronic ethanol increases NK activity in vivo in rat lymphocytes in the liver. ethanol might stimulate NK activity of immune effectors against liver cells. In this study, we have isolated large granular lymphocytes from rat hepatic sinusiods, and determined an increase in their ability to bind to, and lyse specific target cells,when treated with ethanol for two weeks. Endothelial cells, as well as liver non-parenchymal cells, are susceptible targets for these lymphocytes. To assess this finding in humans, we will examine the NK activity of human circulating lymphocytes, in each of the following groups of patients: a-Chronic alcoholics who are still drinking; b-Chronic alcoholics recently withdrawn from dependency; c-Alcoholics with no recent drinking history; d-Non-alcoholic cirrhotics; e-normal healthy volunteers; and f-Alcoholic Cirrhotics. We will measure the effector-to- target binding and effector-to-target lysing ratios. Human endothelial cell lines as well as hepatoma cell lines will be used as targets. We will measure perforin mRNA levels in the lymphocytes by molecular probing. We intend to verify the involvement of perforin as a mediator of increased NK activity, and correlate it with binding and lysing activity. The effect of ethanol on circulating human lymphocytes has been determined, though contradictory, and not in correlation with perforin levels. The implication of this cytolytic protein as a specific mechanism of liver cell killing has clinical relevance in regards to the potential inhibition of liver cell injury by ethanol, as to what pertains to NK cell mediated damage.